Our major objective is to demonstrate that heart wall motion abnormalities characterized by early shortening/late lengthening trigger in the epicardium, local inflammation, reactive oxygen species generation, matrix metalloproteinase (MMP) activation and fibrillar collagen degradation leading to adverse chamber remodeling. Wall motion abnormalities secondary to dysynchronous contraction of the left ventricle (LV) as seen in heart failure reduce ejection fraction and promote remodeling. Similar changes occur in animal models of anterior LV wall epicardial pacing whereby adverse remodeling is characterized by thinning at the pacing site and hypertrophy of the posterior wall. Local strain patterns demonstrate early shortening and late systolic lengthening in the early activated areas (anterior wall) and early lengthening and subsequent shortening of the posterior wall. Preliminary data indicates that anterior wall pacing yields localized evidence for epicardial leucocyte (likely neutrophil) mediated inflammation, activation of MMPs, reactive oxygen species generation (ROS) and collagen degradation. We propose that the mechanism responsible for inflammation/injury is the local expression of adhesion molecules in the microvasculature secondary to alterations in coronary venule blood flow patterns. Four aims are proposed. Aim 1 will test the hypothesis that pacing induced early shortening leads to the local expression of adhesion molecules in coronary venules, trapping of leucocytes, generation of ROS, pro-MMP activation and fibrillar collagen degradation in the epicardium. Aim 2 will test the hypothesis that early shortening regions of the LV demonstrate abnormal epicardial systolic tissue volume changes and modified patterns of epicardial venular blood flow. Aim 3 will test the hypothesis that leucocyte generated ROS structurally modifies pro-MMP-9 in vitro and in vivo. Aim 4 will test the hypothesis that long- term LV wall motion abnormalities induce adverse chamber remodeling characterized by epicardial wall thinning in areas associated with early shortening. A variety of cardiac mechanics, intravital microscopy, proteomics, biochemical and histological methods are to be used. Results from the proposed studies should aid in our understanding of how ventricular dysynchrony as seen in patients with heart failure and left bundle branch block leads to the development of adverse chamber remodeling and loss of contractile function. Anticipated outcome from the proposed studies may also aid clinicians in optimizing cardiac resynchronization therapy. PUBLIC HEALTH RELEVANCE The proposed research addresses an important clinical problem related to how, when the heart does not contract in unison it develops structural and functional abnormalities that are detrimental in nature. These abnormalities are frequently seen in patients with heart failure and our observations indicate that an underlying inflammatory process may explain these adverse changes.